APRIL (A PRoliferation Inducing TNF Ligand, also known as TALL-2) and BAFF (also known as BLys, TALL-1) are closely related ligands of the TNF superfamily. They share two receptors, BCMA and TACI, whereas BAFF binds to a third receptor BAFF-R (also known as BR3) (Kalled, S. L., Ambrose, C. & Hsu, Y. M., Curr Dir Autoimmun 8, 206-42, 2005). BAFF-R, TACI and BCMA are predominantly expressed on B cells, in line with the role of these two TNF-ligands in humoral immune responses. The BAFF/BAFF-R pathway is crucial for maturation of peripheral B cells, and participates also in humoral responses by providing B cell co-stimulation and inducing Ig switch. APRIL has no obvious role in B cell development, but, like BAFF, is involved in humoral responses (Castigli, E. et al., Proc Natl Acad Sci USA 101, 3903-8, 2004). Dysregulation of the BAFF/APRIL pathways has been associated with several autoimmune diseases (Mackay, F., Sierro, F., Grey, S. T. & Gordon, T. P., Curr Dir Autoimmun 8, 243-65, 2005).
In addition to a role in autoimmune pathologies, APRIL and BAFF are implicated in the development of tumors (Mackay, F. & Tangye, S. G., Curr Opin Pharmacol 4, 347-54, 2004). In animal models, APRIL and BAFF over-expression induces development of B cell neoplasia. The involvement of these two TNF ligands in B cell tumors has been substantiated with human cell lines. Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) cell lines were reported to aberrantly express these two TNF ligands, conferring an in vitro survival/proliferative advantage. In patients, the aberrant expression of BAFF and APRIL was confirmed by an elevated seric concentration.
Recently, APRIL binding to the sulfated glycosaminoglycan side chains of proteoglycans was demonstrated (Ingold, K. et al., J Exp Med 201, 1375-83, 2005). In contrast, BAFF does not bind proteoglycans, raising questions on the role of proteoglycans in APRIL function.